The integrins are α/β heterodimeric cell surface receptors involved in numerous cellular processes from cell adhesion to gene regulation. Hynes, R. O., Cell, 1992, 69:11–25; Hemler, M. E., Annu. Rev. Immunol., 1990, 8:365–368. Several integrins have been implicated in disease processes and have generated widespread interest as potential targets for drug discovery. Sharar, S. R. et al., Springer Semin. Immunopathol., 1995, 16:359–378. In the immune system integrins are involved in leukocyte trafficking, adhesion and infiltration during inflammatory processes. Nakajima, H. et al., J. Exp. Med., 1994, 179:1145–1154. Differential expression of integrins regulates the adhesive properties of cells and different integrins are involved in different inflammatory responses. Butcher, E. C. et al., Science, 1996, 272:60–66. The alpha4 integrins (i.e. alpha4beta1 (α4β1) and alpha4beta7 (α4β-7)) are expressed primarily on monocytes, lymphocytes, eosinophils, basophils, and macrophages but not on neutrophils. Elices, M. J. et al., Cell, 1990, 60:577–584. The primary ligands for α4 integrins are the endothelial surface proteins mucosal addressin cell adhesion molecule (MAdCAM) and vascular cell adhesion molecule (VCAM) with lower affinity. Makarem, R. et al., J. Biol. Chem., 1994, 269:4005–4011. The binding of the α4β7 or α4β1 to MAdCAM and/or VCAM expressed on high endothelial venules (HEVs) at sites of inflammation results in firm adhesion of the leukocyte to the endothelium followed by extravasation into the inflamed tissue. Chuluyan, H. E. et al., Springer Semin. Immunopathol., 1995, 16:391–404.
Monoclonal antibodies directed against α4β1, α4β7, MAdCAM or VCAM have been shown to be effective modulators in animal models of chronic inflammatory diseases such as asthma (Laberge, S. et al., Am. J. Respir. Crit. Care Med., 1995, 151:822–829.), rheumatoid arthritis (RA; Barbadillo, C. et al., Springer Semin. Immunopathol., 1995, 16:375–379), colitis (Viney et al, J. Immunol., 1996, 157: 2488–2497) and inflammatory bowel diseases (IBD; Podalski, D. K., N. Eng. J. Med., 1991, 325:928–937; Powrie, F. et al., Ther. Immunol., 1995, 2:115–123). While antibodies can be effective inhibitors of alpha-4 integrins, they are inherently difficult and expensive to manufacture. They are also not orally bioavailable and inconveniently require administration by injection from a physician or other qualified healthcare giver.
In an attempt to find more convenient treatments, many types of small molecules have been made to inhibit binding interaction of alpha-4 integrins with their ligands, a promising example of which are phenylalanine derivatives such as those described in U.S. Pat. No. 6,410,781, U.S. Pat. No. 6,229,011, U.S. Pat. No. 6,329,372, EP 1,270,547, WO 01/68,586 and WO 99/36,393. A particular type of potent alpha-4 integrin inhibitor are tyrosine compounds described in U.S. Pat. No. 6,469,047 which are derivatized at the hydroxyl group to form a carbamate. A representative compound disclosed in U.S. Pat. No. 6,469,047 is incorporates a
tyrosine residue conjugated to a morpholino heterocycle by way of a carbamate linkage. The carbamates are potent inhibitors of alpha-4 integrins but have been shown to metabolize rapidly in vivo yielding a phenoxy metabolite and thereby having a short half life.

Accordingly, there remains a need for small molecule inhibitors of alpha-4 integrins that are resistant to metabolism having prolonged in vivo half-life.